Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods

Abstract

The present invention also relates to carvedilol free base, salts, anhydrous forms, or solvates thereof, corresponding pharmaceutical compositions or controlled release formulations, and methods delivery of carvedilol forms to the lower gastrointestingal tract or methods to treat cardiovascular diseases, which may include, but are not limited to hypertension, congestive heart failure, and angina. The present invention relates to control release formulations, which comprise various cavedilol forms, which may include, but are not limited to carvedilol free base and corresponding carvedilol salts, anhydrous forms or solvates thereof.

1 . A controlled release delivery formulation or device, comprising: 
 a core containing a carvedilol free base, salt, solvate or anhydrous form thereof;    a release modifying agent; and    an outer coating covering the core; 
 wherein thickness of the outer coating is adapted: 
 for substantial impermeability to entry of fluid present in an environment of use and for substantial impermeability toward release of the carvedilol free base, salt, solvate or anhydrous form thereof during a predetermined dosing interval; and  
 for a controlled release dispensing exit of the carvedilol free base, salt, solvate or anhydrous form thereof after the predetermined dosing interval;  
 
 wherein the outer coating includes at least one orifice in at least one face area of the controlled delivery device extending substantially through the outer coating but not penetrating the core that communicates from the environment of use to the core allowing for release of the carvedilol free base, salt, solvate or anhydrous form thereof into the environment of use; 
 wherein the at least one orifice in the at least one face area of the controlled release delivery device has a substantially dependent rate limiting release factor dependent upon exit of the carvedilol free base, salt, solvate or anhydrous form thereof from the at least one orifice via dissolution, diffusion or erosion; and  
 wherein the release modifying agent enhances or hinders release of the carvedilol free base, salt, solvate or anhydrous form thereof depending upon solubility or effective solubility of the carvedilol free base, salt, solvate or anhydrous form thereof in the environment of use.  
 
   
     
     
         2 . A controlled release delivery formulation or device, comprising: 
 a core containing a carvedilol free base, salt, solvate or anhydrous form thereof;    a release modifying agent, and    an outer coating layer covering the core; 
 wherein the outer coating layer: 
 is substantially impermeable to the entrance of gastrointestinal fluid and substantially impermeable to release of the carvedilol free base, salt, solvate or anhydrous form thereof agent during a predetermined dosing interval; and  
 is adapted for a controlled release dispensing exit of the carvedilol free base, salt, solvate or anhydrous form thereof after the predetermined dosing interval;  
 
 wherein the outer coating layer includes at least one orifice for release of the carvedilol free base, salt, anhydrous form or solvate thereof during the dosing interval; 
 wherein the orifice extends substantially completely through the coating but not penetrating the core,  
 wherein a release rate limiting step is dependent substantially on exit of the carvedilol free base, salt, anhydrous form or solvate thereof through the at least one orifice via dissolution, diffusion or erosion of the carvedilol free base, salt, anhydrous form or solvate thereof in solution or suspension, and  
 wherein the release modifying agent enhances or hinders release of the carvedilol free base, salt, anhydrous form or solvate thereof depending upon solubility or effective solubility in gastrointestinal fluid.  
 
   
     
     
         3 . The controlled release formulation according to  claim 1 , wherein the solubility enhanced carvedilol free base, salt, solvate or anhydrous form thereof include an acid addition salt of carvedilol free base or carvedilol salt, solvate and/or anhydrous forms thereof.  
     
     
         4 . The controlled release formulation or device according to  claim 3 , wherein the acid addition salt of carvedilol free base, salt, solvate or anhydrous form thereof is an acid addition salt formed from a mineral acid or an organic acid.  
     
     
         5 . The controlled release formulation according to  claim 4 , wherein the mineral acid is selected from hydrobromic acid, hydrochloric acid, phosphoric or sulphuric acid, and the organic acid is selected from methansulphuric acid, tartaric acid, maleic acid, acetic acid, citric acid, benzoic acid and the like.  
     
     
         6 . The controlled release formulation or device according to  claim 1 , wherein the carvedilol salt, solvate or anhydrous form thereof is selected from the group consisting of carvedilol mandelate, carvedilol lactate, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, carvedilol mesylate, carvedilol phosphate, carvedilol citrate, carvedilol hydrogen bromide, carvedilol oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide, carvedilol benzoate, or corresponding solvates thereof.  
     
     
         7 . The controlled release formulation or device according to  claim 1 , wherein the carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen phosphate methanol solvate, carvedilol hydrobromide monohydrate, carvedilol hydrobromide dioxane solvate, carvedilol hydrobromide 1-pentanol solvate, carvedilol hydrobromide 2-methyl-1-propanol solvate, carvedilol hydrobromide trifluoroethanol solvate, carvedilol hydrobromide 2-propanol solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol hydrobromide n-propanol solvate #2, carvedilol hydrobromide anhydrous forms or anhydrous forms, carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide dioxane solvate, carvedilol monocitrate monohydrate, carvedilol mandelate, carvedilol lactate, carvedilol hydrochloride, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, or corresponding anhydrous forms, solvates thereof.  
     
     
         8 . The controlled release formulation or device according to  claim 7 , wherein the carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen phosphate methanol solvate.  
     
     
         9 . The controlled release formulation or device according to  claim 8 , wherein the carvedilol salt, solvate or anhydrous form is carvedilol dihydrogen phosphate hemihydrate.  
     
     
         10 . The controlled release formulation or device according to  claim 1 , wherein the outer coating further is coated with materials selected from the group consisting of a film coat and a pH sensitive polymer.  
     
     
         11 . The controlled release formulation or device according to  claim 1 , wherein the controlled release delivery device has two face areas.  
     
     
         12 . The controlled release formulation or device according to  claim 11 , wherein at least one of the two face areas contains an aperture or orifice.  
     
     
         13 . The controlled release formulation or device according to  claim 1 , wherein the at least one orifice has an area from at least about 10 percent to at least about 60 percent in the face area(s) of the controlled release delivery device.  
     
     
         14 . The controlled release formulation or device according to  claim 13 , wherein the at least one orifice has a diameter which is about 30 percent of the diameter of the controlled release delivery device.  
     
     
         15 . The controlled release formulation or device according to  claim 1 , wherein the at least one orifice is an aperture, hole, passage way or outlet.  
     
     
         16 . The controlled release formulation or device according to  claim 15 , wherein the orifice has an aperture diameter size range or orifice diameter size range from at least about 0.0 mm to at least about 7.0 mm.  
     
     
         17 . The controlled release formulation or device according to  claim 16 , wherein the orifice has an aperture diameter size or orifice diameter size of at least about 6.0 mm.  
     
     
         18 . The controlled release delivery formulation or device according to  claim 1 , wherein the delivery device is in an oral dosage form.  
     
     
         19 . The controlled release formulation or device according to  claim 18 , wherein the oral dosage form is a tablet dosage form.  
     
     
         20 . The controlled release formulation or device according to  claim 19 , wherein the tablet dosage form is selected from a single core tablet matrix dosage form or a bilayer tablet dosage form.  
     
     
         21 . The controlled release formulation or device according to  claim 20 , wherein the single core tablet matrix dosage form has an immediate release core.  
     
     
         22 . The controlled release formulation or device according to  claim 20 , wherein the single core tablet matrix dosage form has orifices or apertures on at least two faces with a diameter range from 0.0 mm to 4 mm.  
     
     
         23 . The controlled release formulation or device according to claim  20 , wherein the oral tablet dosage form is a bilayer tablet dosage form.  
     
     
         24 . The controlled release formulation or device according to  claim 23 , wherein the bilayer tablet dosage form has two separate sequential layers.  
     
     
         25 . The controlled release formulation or device according to  claim 24 , wherein one of the two separate sequential layers is defined as a tablet core matrix.  
     
     
         26 . The controlled release formulation or device according to  claim 25 , wherein the two separate sequential layers are comprised of an immediate release layer and a modified release layer.  
     
     
         27 . A method of treating cardiovascular diseases, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation or device according to  claim 1 .  
     
     
         28 . The method of treating cardiovascular diseases of  claim 27 , wherein cardiovascular diseases are selected from the group consisting of hypertension, atherosclerosis, congestive heart failure and angina.  
     
     
         29 . A method of treating hypertension, congestive heart failure, atherosclerosis, or angina which comprises administering to a subject in need thereof an effective amount of the controlled release formulation or device according to  claim 1 .  
     
     
         30 . A method of treating hypertension, congestive heart failure, atherosclerosis, or angina which comprises administering to a subject in need thereof an effective amount of the controlled release formulation or device according to  claim 29 .  
     
     
         31 . A method of delivering carvedilol to lower gastrointestinal tract of a subject in need thereof, which comprises administering a controlled release device or formulation or device according to  claim 1 .  
     
     
         32 . A method of delivering carvedilol to lower gastrointestinal tract of a subject in need thereof, which comprises administering a controlled release device or formulation or device according to  claim 2 .  
     
     
         33 . A controlled release delivery formulation or device, comprising: 
 a hydrophilic matrix core containing a carvedilol free base, salt, solvate or anhydrous form thereof;    a film coat layer covering the hydrophilic matrix core to form a film coated hydrophilic matrix core; 
 wherein the film coat layer is comprised of enteric coating materials or release modifying agents;  
 wherein thickness of the film coat layer is adapted: 
 for substantial impermeability to entry of fluid present in an environment of use and for substantial impermeability toward release of the carvedilol free base, salt, solvate or anhydrous form thereof in the film coat layer during a predetermined dosing interval; and  
 for a controlled release dispensing exit of the carvedilol free base, salt, solvate or anhydrous form thereof in the film coat layer after the predetermined dosing interval;  
 wherein the enteric coating materials or release modifying agents enhance release or hinder release of the carvedilol free base, salt, solvate or anhydrous form thereof depending upon solubility or effective solubility of the carvedilol free base, salt, solvate or anhydrous form thereof in the environment of use; and  
 
   an outer immediate release drug coating layer covering the film coated hydrophilic matrix core; 
 wherein the outer immediate release drug coating layer is comprised of carvedilol free base, salt, solvate or anhydrous form thereof;  
 wherein the outer immediate release drug coating layer includes at least one orifice or aperture in at least one face area of the controlled delivery formulation or device extending substantially through the outer immediate release drug coating layer and the film coat layer but not penetrating the hydrophilic matrix core that communicates from the environment of use to the hydrophilic matrix core allowing for release of the carvedilol free base, salt, solvate or anhydrous form thereof from the hydrophilic matrix core, the film coat layer and the outer immediate release drug coating layer into the environment of use; and  
 wherein the at least one orifice or aperture in the at least one face area of the controlled release delivery formulation or device has a substantially dependent rate limiting release factor dependent upon exit of the carvedilol free base, salt, solvate or anhydrous form thereof from the hydrophilic matrix core, the film coat layer, and from the outer immediate release drug coating layer from the at least one orifice via dissolution, diffusion or erosion.  
   
     
     
         34 . A controlled release delivery formulation or device, comprising: 
 a hydrophilic matrix core containing a carvedilol free base, salt, solvate or anhydrous form thereof;    a film coat layer formed covering the hydrophilic matrix core to form a film coated hydrophilic matrix core; 
 wherein the film coat layer is comprised of enteric coating materials or release modifying agents; and  
   an outer immediate release drug coating layer covering the film coated hydrophilic matrix core; 
 wherein the outer immediate release drug coating layer: 
 is comprised of carvedilol free base, salt, solvate or anhydrous form thereof;  
 is substantially permeable to the entrance of gastrointestinal fluid and substantially permeable to release of the carvedilol free base, salt, solvate or anhydrous form thereof during a predetermined dosing interval; and  
 includes at least one orifice or aperture for release of the carvedilol free base, salt, anhydrous form or solvate thereof from the hydrophilic matrix core, the film coat layer, and the outer immediate release drug coating layer during the dosing interval; 
 wherein the at least one orifice or aperture extends substantially completely through the outer immediate release drug coating layer and the film coat layer but not penetrating the hydrophilic matrix core,  
 
 
 wherein the film coat layer is adapted for a controlled release dispensing exit of the carvedilol free base, salt, solvate or anhydrous form thereof after the predetermined dosing interval;  
 wherein a release rate limiting step is dependent substantially on exit of the carvedilol free base, salt, anhydrous form or solvate thereof which occurs through the at least one orifice via dissolution, diffusion or erosion of the carvedilol free base, salt, anhydrous form or solvate thereof from the hydrophilic matrix core, the film coat layer and the outer immediate release drug coating layer in solution or suspension, and 
 wherein each enteric coating material or release modifying agent enhances or hinders release of the carvedilol free base, salt, anhydrous form or solvate thereof depending upon solubility or effective solubility in gastrointestinal fluid.  
 
   
     
     
         35 . The controlled release formulation according to  claim 33 , wherein the carvedilol free base, salt, solvate or anhydrous form thereof in the hydrophilic matrix core or the outer immediate release drug coating layer include an acid addition salt of carvedilol free base or carvedilol salt, solvate and/or anhydrous forms thereof.  
     
     
         36 . The controlled release formulation or device according to  claim 35 , wherein the acid addition salt of carvedilol free base, salt, solvate or anhydrous form thereof is an acid addition salt formed from mineral acids or organic acids.  
     
     
         37 . The controlled release formulation according to  claim 36 , wherein the mineral acid is selected from hydrobromic acid, hydrochloric acid, phosphoric or sulphuric acid, and the organic acid is selected from methansulphuric acid, tartaric acid, maleic acid, acetic acid, citric acid, benzoic acid and the like.  
     
     
         38 . The controlled release formulation or device according to  claim 33 , wherein the carvedilol salt, solvate or anhydrous form thereof is selected from the group consisting of carvedilol mandelate, carvedilol lactate, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, carvedilol mesylate, carvedilol phosphate, carvedilol citrate, carvedilol hydrogen bromide, carvedilol oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide, carvedilol benzoate, or corresponding solvates thereof.  
     
     
         39 . The controlled release formulation or device according to  claim 33 , wherein the carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen phosphate methanol solvate, carvedilol hydrobromide monohydrate, carvedilol hydrobromide dioxane solvate, carvedilol hydrobromide 1-pentanol solvate, carvedilol hydrobromide 2-methyl-1-propanol solvate, carvedilol hydrobromide trifluoroethanol solvate, carvedilol hydrobromide 2-propanol solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol hydrobromide n-propanol solvate #2, carvedilol hydrobromide anhydrous forms or anhydrous forms, carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide dioxane solvate, carvedilol monocitrate monohydrate, carvedilol mandelate, carvedilol lactate, carvedilol hydrochloride, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, or corresponding anhydrous forms, solvates thereof.  
     
     
         40 . The controlled release formulation or device according to  claim 39 , wherein the carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen phosphate methanol solvate.  
     
     
         41 . The controlled release formulation or device according to  claim 40 , wherein the carvedilol salt, solvate or anhydrous form is carvedilol dihydrogen phosphate hemihydrate.  
     
     
         42 . The controlled release formulation or device according to  claim 33 , wherein the outer immediate release drug coating layer further is coated with materials selected from the group consisting of a film coat and a pH sensitive polymer.  
     
     
         43 . The controlled release delivery formulation or device according to  claim 33 , wherein the delivery device is in an oral dosage form.  
     
     
         44 . The controlled release formulation or device according to  claim 43 , wherein the oral dosage form is a tablet dosage form.  
     
     
         45 . The controlled release formulation or device according to  claim 44 , wherein the tablet dosage form is selected from a single core tablet matrix dosage form, a bilayer tablet dosage form or a trilayer tablet dosage form.  
     
     
         46 . The controlled release formulation or device according to  claim 33 , wherein the at lease one orifice or aperture has an orifice or aperture or orifice diameter size range from at least about 0.0 mm to at least about 7.0 mm.  
     
     
         47 . The controlled release formulation or device according to  claim 46 , wherein the orifice or aperture diameter size is in a range of at least about 5.0 mm to at least about 6.0 mm.  
     
     
         48 . The controlled release formulation or device according to  claim 33 , wherein the outer immediate release drug coating layer further includes materials selected from enteric coating materials, release modifying agents or pharmaceutically acceptable carriers, adjuvants and excipients.  
     
     
         49 . The controlled release formulation or device according to  claim 48 , wherein the materials contained in the outer immediate release drug coating layer allows for the immediate release of the carvedilol free base, salt, solvate or anhydrous form thereof contained in the outer immediate release drug coating layer.  
     
     
         50 . A method of treating cardiovascular diseases, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation or device according to  claim 33 .  
     
     
         51 . The method of treating cardiovascular diseases of  claim 50 , wherein cardiovascular diseases are selected from the group consisting of hypertension, atherosclerosis, congestive heart failure and angina.  
     
     
         52 . A method of treating cardiovascular diseases, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation or device according to  claim 34 .  
     
     
         53 . The method of treating cardiovascular diseases of  claim 52 , wherein cardiovascular diseases are selected from the group consisting of hypertension, atherosclerosis, congestive heart failure and angina.